DNA Damage Induced by Alkylating Agents and Repair Pathways

Figure 1

Pathways for DNA damage induced by methylating agents. (a) 𝑂⁶-methylguanine-DNA methyltransferase (MGMT) removes the methyl adduct from 𝑂⁶MeG in one step. If left unrepaired, 𝑂⁶MeG:C ambiguous pairs or 𝑂⁶MeG:T mismatch pairs can form during replication. In the next round of replication, 𝑂⁶MeG:T pairs can become A:T transition mutations. (b) 𝑂⁶MeG:T and 𝑂⁶MeG:C pairs are recognized by the mismatch repair (MMR) system, which creates a single-strand break (SSB), cause replication arrest, and finally leads to a double-strand break (DSB). 𝑂⁶MeG:T/C does not induce cell cycle arrest at the first G₂/M DNA damage checkpoint, but G₂/M arrest is commonly observed in the second cell cycle. (c) Homologous recombination (HR) and nonhomologous end joining (NHEJ) may play a role in the repair of DSBs. 𝑁-alkylations are repaired by either (d) base excision repair (BER), or (e) AlkB homologues, and if not repaired, DSBs occur.